L. Framarin

New Pharmacologic Agents That Target Inflammation and Fibrosis in Nonalcoholic Steatohepatitis-Related Kidney Disease.

&NA; Epidemiologic data show an association between the prevalence and severity of nonalcoholic fatty liver disease and the incidence and stage of chronic kidney disease (CKD); furthermore, nonalcoholic steatohepatitis (NASH)‐related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver‐kidney transplantation, and a poorer renal outcome than cirrhosis of other etiologies even after simultaneous liver‐kidney transplantation. These data suggest that NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are targeted incompletely by current treatments. We reviewed therapeutic approaches to late preclinical/early clinical stage of development in NASH and/or CKD, focusing on anti‐inflammatory and antifibrotic treatments, which could slow the progression of both disease conditions. Renin inhibitors and angiotensin‐converting enzyme‐2 activators are new renin‐angiotensin axis modulators that showed incremental advantages over angiotensin‐converting enzyme inhibitors/angiotensin‐receptor blockers in preclinical models. Novel, potent, and selective agonists of peroxisome proliferator‐activated receptors and of farnesoid X receptor, designed to overcome limitations of older compounds, showed promising results in clinical trials. Epigenetics, heat stress response, and common effectors of redox regulation also were subjected to intensive research, and the gut was targeted by several approaches, including synbiotics, antilipopolysaccharide antibodies, Toll‐like receptor‐4 antagonists, incretin mimetics, and fibroblast growth factor 19 analogs. Promising anti‐inflammatory therapies include inhibitors of NOD‐like receptor family, pyrin domain containing 3 inflammasome, of nuclear factor‐&kgr;B, and of vascular adhesion protein‐1, chemokine antagonists, and solithromycin, and approaches targeting common profibrogenic pathways operating in the liver and the kidney include galectin‐3 antagonists, and inhibitors of rho‐associated protein kinase and of epidermal growth factor activation. The evidence, merits, and limitations of each approach for the treatment of NASH and CKD are discussed.

Gut Microbiota, Hypertension and Chronic kidney Disease: recent advances

A large number of different microbial species populates intestine. Extensive research has studied the entire microbial population and their genes (microbiome) by using metagenomics, metatranscriptomics and metabolomic analysis. Studies suggest that the imbalances of the microbial community causes alterations in the intestinal homeostasis, leading to repercussions on other systems: metabolic, nervous, cardiovascular, immune. These studies have also shown that alterations in the structure and function of the gut microbiota play a key role in the pathogenesis and complications of Hypertension (HTN) and Chronic Kidney Disease (CKD). Increased blood pressure (BP) and CKD are two leading risk factors for cardiovascular disease and their treatment represents a challenge for the clinicians. In this Review, we discuss mechanisms whereby gut microbiota (GM) and its metabolites act on downstream cellular targets to contribute to the pathogenesis of HTN and CKD, and potential therapeutic implications.

LCT-13910C > T polymorphism-associated lactose malabsorption and risk for colorectal cancer in Italy

BACKGROUND The activity of epithelial lactase (LCT) associates with a polymorphism 13910 bp upstream the LCT-encoding gene (LCT-13910C>T). The relationship between LCT-13910C>T polymorphism and risk for colorectal cancer is unclear. AIMS We examined the relationship between the LCT-13910C>T polymorphism causing lactose intolerance and risk for colorectal cancer/polyps onset in the Italian population. PATIENTS AND METHODS 793 subjects (306 with colorectal cancer, 176 with polyps and 311 controls) were genotyped for the LCT-13910C>T variant by TaqMan real time-PCR. RESULTS Lactose malabsorption linked to the CC genotype did not associate with an increased risk for either colorectal cancer (OR=1.041; 95% CI=0.751-1.442; p=0.868) or polyps (OR=0.927; 95% CI=0.630-1.363; p=0.769). There was no association with colorectal cancer/polyps site. 60% of the subjects overall bore the CC genotype. CONCLUSION In the Italian population the LCT-13910C>T polymorphism is not associated to the risk for colorectal cancer or polyps.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat

&NA; The loss‐of‐function rs4374383 G > A variant in Myeloid‐epithelial‐reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non‐immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed‐up 305 healthy nonobese nondiabetic, metabolic syndrome‐free insulin sensitive participants in a population‐based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers. An independent cohort of 69 biopsy‐proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP‐1, and of Nuclear Factor (NF)‐&kgr;B activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9‐year incident NAFLD (OR:0.48,95%CI:0.26‐0.79) and diabetes (OR: 0.47, 95% CI: 0.19‐0.87). In the cross‐sectional cohort, MERTK A‐allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A‐allele carriers showed lower resistin and MCP‐1 responses, milder MNC NF‐&kgr;B activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro‐inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.

Altered Gut Microbiota in Type 2 Diabetes: Just a Coincidence?

Purpose of ReviewIn the last decade many studies have suggested an association between the altered gut microbiota and multiple systemic diseases including diabetes. In this review, we will discuss potential pathophysiological mechanisms, the latest findings regarding the mechanisms linking gut dysbiosis and type 2 diabetes (T2D), and the results obtained with experimental modulation of microbiota.Recent FindingsIn T2D, gut dysbiosis contributes to onset and maintenance of insulin resistance. Different strategies that reduce dysbiosis can improve glycemic control.SummaryEvidence in animals and humans reveals differences between the gut microbial composition in healthy individuals and those with T2D. Changes in the intestinal ecosystem could cause inflammation, alter intestinal permeability, and modulate metabolism of bile acids, short-chain fatty acids and metabolites that act synergistically on metabolic regulation systems contributing to insulin resistance. Interventions that restore equilibrium in the gut appear to have beneficial effects and improve glycemic control. Future research should examine in detail and in larger studies other possible pathophysiological mechanisms to identify specific pathways modulated by microbiota modulation and identify new potential therapeutic targets.